A single mutation (Arg206His) within the kinase domain of one (ACVR1/ALK2) of the four human bone morphogenetic protein (BMP) receptors has been linked to a catastrophic disorder of secondary (heterotopic) bone formation known to mankind. As a result of the substitution with histidine, all children presenting with features of classic FOP (Fibrodysplasia Ossificans Progressiva) eventually become encased in, and their movement blocked by, a second heterotopic skeleton. The disorder has long been associated with dysregulation of BMP signaling in soft tissues (skeletal muscle, tendon, ligament, fascia) that were transformed into ribbons, sheets and plates of heterotopic bone via an endochondral process. In addition to the common R206H mutation linked to the classic form of FOP (71/88 patients), other dysregulating mutations have been identified in ACVR1/ALK2 that lead to atypical (8/88) and variant (9/88) forms of FOP.
Recent screening studies have identified compounds that inhibit BMP signaling by ALK2. However, these compounds also inhibit kinases from multiple signaling pathways rather significantly and thus are unsuitable for clinical applications.
Thus, it would be beneficial to identify compounds or molecules that inhibit the ALK2 kinase without significantly affecting any other kinases. The present invention provides a useful method for the identification of putative inhibitors of activin-like receptor kinases that destabilize the proteins by binding at a site other than the highly conserved ATP-binding cleft or active site. The present invention is also directed to compounds identified by the methods described herein.